Research and Development Division (J.C.-C., M.D.G., N.K.P., D.G., R.D.K.), Jesse Brown Veterans Affairs Medical Center, and Section of Endocrinology, Diabetes, and Metabolism (J.C.-C., M.D.G., N.K.P., D.G., R.D.K.), Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612; Department of Cell Biology, Physiology, and Immunology (M.D.G., R.M.L.), University of Cordoba, Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofia and Centros de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutricion, Cordoba 14014, Spain; and Division of Endocrinology, Diabetes, and Metabolism (M.A., R.S.), School of Medicine, Johns Hopkins University, Baltimore, Maryland 21218.
Endocrinology. 2014 Mar;155(3):726-35. doi: 10.1210/en.2013-1825. Epub 2013 Dec 16.
Developmental models of GH deficiency (GHD) and excess indicate that GH is positively associated with β-cell mass. Therefore, the reduction in GH levels observed with age and weight gain may contribute to the age-related decline in β-cell function. To test this hypothesis, β-cell mass and function were assessed in a mouse model of adult-onset, isolated GHD (AOiGHD). β-Cell mass did not differ between low-fat (LF)-fed AOiGHD and controls. However, high fat-fed AOiGHD mice displayed impaired expansion of β-cell mass and a reduction of bromodeoxyuridine-labeled islet cells, whereas in vitro β-cell function (basal and glucose-stimulated insulin secretion [GSIS]) did not differ from controls. In contrast, duration of AOiGHD differentially altered in vitro β-cell function in LF-fed mice. Specifically, islets from young LF-fed AOiGHD mice showed significant reductions in insulin content and basal insulin secretion, but GSIS was similar to that of controls. A similar islet phenotype was observed in a developmental model of isolated GHD (GH-releasing hormone knockout). Given that LF- and high fat-fed AOiGHD mice, as well as GH-releasing hormone knockout mice, display improved insulin sensitivity, islet changes may be due to reduced insulin demand, rather than primary β-cell dysfunction. However, islets from older LF-fed AOiGHD mice exhibited impaired GSIS, associated with reduced expression of genes important to maintain glucose sensing, suggesting that factors secondary to AOiGHD can alter β-cell function with age. AOiGHD mice exhibited postprandial hypertriglyceridemia and increased pancreatic expression of lipid/inflammatory stress response genes (activating transcription factor 3 and peroxisome proliferator activator receptor β/δ). Therefore, we speculate that these changes may initially protect the AOiGHD β-cell, but with age, lipotoxicity may impair β-cell function.
生长激素缺乏症（GHD）和生长激素过多的发育模型表明，生长激素与β细胞质量呈正相关。因此，随着年龄的增长和体重的增加而观察到的生长激素水平的降低可能导致β细胞功能的年龄相关性下降。为了验证这一假说，在成年发病、孤立性 GHD（AOiGHD）的小鼠模型中评估了β细胞质量和功能。低脂（LF）喂养的 AOiGHD 和对照组之间的β细胞质量没有差异。然而，高脂喂养的 AOiGHD 小鼠显示β细胞质量扩张受损，溴脱氧尿苷标记的胰岛细胞减少，而体外β细胞功能（基础和葡萄糖刺激胰岛素分泌[GSIS]）与对照组没有差异。相比之下，AOiGHD 的持续时间在 LF 喂养的小鼠中不同地改变了体外β细胞功能。具体来说，年轻 LF 喂养的 AOiGHD 小鼠的胰岛胰岛素含量和基础胰岛素分泌显著减少，但 GSIS 与对照组相似。在孤立性 GHD（生长激素释放激素敲除）的发育模型中也观察到类似的胰岛表型。鉴于 LF 喂养和高脂喂养的 AOiGHD 小鼠以及生长激素释放激素敲除小鼠表现出改善的胰岛素敏感性，胰岛变化可能是由于胰岛素需求减少，而不是原发性β细胞功能障碍。然而，年长 LF 喂养的 AOiGHD 小鼠的胰岛 GSIS 受损，与维持葡萄糖感应重要的基因表达减少有关，这表明 AOiGHD 后的因素会随着年龄的增长而改变β细胞功能。AOiGHD 小鼠表现出餐后高甘油三酯血症和胰腺脂质/炎症应激反应基因（激活转录因子 3 和过氧化物酶体增殖物激活受体β/δ）表达增加。因此，我们推测这些变化最初可能会保护 AOiGHD 的β细胞，但随着年龄的增长，脂毒性可能会损害β细胞功能。
